Several factors may contribute to major depressive disorder. These include, but are not limited to: 1) smaller hippocampal volumes (Sheline et al., 1999); 2) decreased levels of brain derived neurotrophic factor (BDNF; Dwivedi et al., 2010); and 3) abnormalities in the serotonin transporter (SERT; Caspi et al, 2003). Of note, preclinical studies indicate that administration of selective serotonin reuptake inhibitors, a common treatment for depression in humans, increase hippocampal BDNF levels and decrease depressive symptoms (Sillaber et al., 2008). Similar to major depressive disorder, methamphetamine (METH) abuse in humans is associated with: 1) smaller hippocampal volumes (Thompson et al., 2004); and 2) depressive symptoms in abstinent users (Glasner-Edwards et al., 2009). Further, preclinical studies have shown experimenter-administered METH leads to decreased hippocampal SERT function and serotonin content (Haughey et al., 2000; Cadet et al., 2009). The potential interaction between SERT function, BDNF, hippocampal volumes, and depressive symptoms after METH use has received little attention. Accordingly, the current proposal will test the hypothesis that the self-administration of METH decreases SERT function and, consequently, contributes to decreases in BDNF levels within the hippocampus. These decreases in BDNF, in turn, may lead to decreases in neurogenesis and cell survival, which may contribute to the loss of hippocampal volume, and increases in depressive symptoms. Of note, preliminary data suggest that both decreases in SERT function and BDNF within the hippocampus occur after as little as 5 d of METH self-administration. The results of these studies have the potential to contribute significantly to the understanding of, an potential therapeutic targets for, the treatment of depression associated with METH abuse.